The goal of the proposal is to determine the potential of a new class of compounds, selective inhibitors of dysregulated proinflammatory cytokines/chemokines, to increase the therapeutic gain for cancer patients receiving radiotherapy for tumors that are known to be radiation resistant (e.g. malignant brain tumors, pancreatic cancer, and lung cancer - stage III/IV). The exploratory proposal builds on our previous discoveries that the lead cytokine/chemokine inhibitor mitigates radiation injury in multiple tissues and the same compound confers an enhancement in radiation tumor growth delay. Two specific aims are planned to confirm the studies in orthotopic tumor models and to elucidate the mechanism of action. In Aim 1, we test the hypothesis that the inhibitor when administered to rats with brain tumors enhances the radiotherapy efficacy and reduces the radiation injury to normal brain. We aim to determine if the therapeutic ratio of a cytokine inhibitor combined with radiation is superior to radiation alone. In Aim 2, we test the hypothesis that the inhibitor suppresses acute proinflammatory cytokines including those produced by activated macrophage in the tumor tissue and reduces neuroinflammation caused by activated microglia in the normal brain following radiation. We aim to elucidate the mechanism of action of a cytokine inhibitor?s effects on the radiation response of tumor and normal brain following single and fractionated radiation. At the completion of these studies we expect that a new paradigm for improving radiation therapy will have been initiated.